WO2019085927A1 - Sel et cristal d'inhibiteur de fgfr4, son procédé de préparation et son utilisation - Google Patents

Sel et cristal d'inhibiteur de fgfr4, son procédé de préparation et son utilisation Download PDF

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WO2019085927A1
WO2019085927A1 PCT/CN2018/112891 CN2018112891W WO2019085927A1 WO 2019085927 A1 WO2019085927 A1 WO 2019085927A1 CN 2018112891 W CN2018112891 W CN 2018112891W WO 2019085927 A1 WO2019085927 A1 WO 2019085927A1
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compound
formula
xrpd pattern
diffraction peaks
salt
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PCT/CN2018/112891
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English (en)
Chinese (zh)
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何雷
李响
林青
陈中科
余俊
杜祖银
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江苏豪森药业集团有限公司
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Priority to CN201880009211.8A priority Critical patent/CN110234649B/zh
Publication of WO2019085927A1 publication Critical patent/WO2019085927A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of crystal forms, and in particular relates to a pharmaceutically acceptable salt of a compound of the formula (I), a crystalline form of a pharmaceutically acceptable salt, a preparation method and use thereof.
  • the fibroblast growth factor receptor belongs to the receptor tyrosine kinase transmembrane receptor and includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4.
  • FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions.
  • FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.
  • FGFR4 a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers can cause critical tyrosine in FGFR4's own cells.
  • FGF19 fibroblast growth factor 19
  • the phosphorylation of the amino acid residue activates multiple downstream signaling pathways in the cell, and these intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis.
  • FGFR4 is overexpressed in many cancers and is a predictor of malignant invasion of tumors. Decreasing and reducing FGFR4 expression can reduce cell proliferation and promote apoptosis.
  • FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.
  • liver cancer ranks first in the world in China, with new and dead patients accounting for about half of the total number of liver cancers worldwide each year. At present, the incidence of liver cancer in China is about 28.7/100,000. In 2012, there were 394,770 new cases, which became the third most serious malignant tumor after gastric cancer and lung cancer.
  • the onset of primary liver cancer is a multi-factor, multi-step complex process with strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve the survival rate of some patients, but only limited patients can undergo surgery, and most patients have a poor prognosis due to recurrence and metastasis after surgery. Sorafenib is the only liver cancer treatment drug approved on the market.
  • FGFR4 is a major carcinogenic factor in liver cancer, and its development of small molecule inhibitors has great clinical application potential.
  • FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia.
  • target related side effects Such as target related side effects.
  • Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition.
  • Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.
  • One aspect of the invention provides a pharmaceutically acceptable salt of a compound of formula (I).
  • a second aspect of the invention provides a crystalline form of the hydrochloride salt of a compound of formula (I).
  • a third aspect of the invention provides a crystalline form of a sulfate salt of a compound of formula (I).
  • a fourth aspect of the invention provides a crystalline form of the methanesulfonate salt of the compound of formula (I).
  • a fifth aspect of the invention provides a crystalline form of a besylate salt of a compound of formula (I).
  • a sixth aspect of the invention provides a crystalline form of the ethanesulfonate salt of the compound of formula (I).
  • a seventh aspect of the invention provides a crystalline form of the oxalate salt of the compound of formula (I).
  • An eighth aspect of the invention provides a crystalline form of the maleate salt of the compound of formula (I).
  • a ninth aspect of the invention provides a crystalline form of the p-toluenesulfonate salt of the compound of formula (I).
  • a tenth aspect of the invention provides a pharmaceutical composition of a pharmaceutically acceptable salt crystalline form of a compound of formula (I).
  • An eleventh aspect of the invention provides a process for the preparation of a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I).
  • the twelfth aspect of the invention provides the use of a pharmaceutically acceptable salt crystalline form of a compound of formula (I).
  • the "pharmaceutically acceptable salt” of the present invention may be any salt as long as it forms a non-toxic salt with the compound of the formula (I).
  • examples include, but are not limited to, salts with various inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, carbonates, bicarbonates, perchloric acids.
  • Salts, etc. salts with organic acids such as citrate, tartrate, fumarate, succinate, maleate, acetate, malate, benzoate, p-toluate, Methanesulfonate, besylate, p-toluenesulfonate, ethanesulfonate, isethionate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, camphorsulfonate, trifluoromethyl Sulfonate, trifluoroacetate, lactate, oxalate, salicylate, phenylacetate, mandelate, formate, acetate, trifluoroacetate, propionate, Oxalate, glycolate, hydroxymaleate, methyl maleate, adipate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, niacin Salt, isonicotinate, cholate, aspartate or glutamate.
  • organic acids
  • the present invention provides a process for the preparation of a pharmaceutically acceptable salt of a compound of formula (I), which is obtained by reacting a compound of formula (I) with an acid in a solvent.
  • the solvent includes an organic solvent or an inorganic solvent selected from the group consisting of an alcohol solvent, a ketone solvent, an ester solvent, dichloromethane, acetonitrile, chloroform, or a mixed solvent thereof, preferably water or ethyl formate.
  • an organic solvent or an inorganic solvent selected from the group consisting of an alcohol solvent, a ketone solvent, an ester solvent, dichloromethane, acetonitrile, chloroform, or a mixed solvent thereof, preferably water or ethyl formate.
  • an organic solvent or an inorganic solvent selected from the group consisting of an alcohol solvent, a ketone solvent, an ester solvent, dichloromethane, acetonitrile, chloroform, or a mixed solvent thereof, preferably water or ethyl formate.
  • a mixed solvent thereof preferably water or ethyl formate.
  • the acid includes an organic acid or inorganic acid including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, perchloric acid, etc.; organic acids include, but are not limited to, citric acid , tartaric acid, fumaric acid, succinic acid, maleic acid, acetic acid, malic acid, benzoic acid, p-toluic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, isethionic acid, 1 -naphthalenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, lactic acid, oxalic acid, salicylic acid, phenylacetic acid, mandelic acid, formic acid,
  • the present invention provides a hydrochloride salt form of the compound of formula (I).
  • the present invention provides the hydrochloride salt form I of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.8, 9.9, 11.0, 16.7 and 25.3;
  • the XRPD pattern of the hydrochloride salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 8.2, 9.9, 11.0, 12.1, 12.4, 13.0, 14.0, 16.7, 18.5, 19.0, 22.3. , 25.3, 25.8, 26.2, and 27.7 diffraction peaks.
  • the present invention provides a process for the preparation of the salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethyl acetate.
  • the present invention provides a salt form II of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.0, 6.5, 15.7 and 23.8.
  • the XRPD pattern of the hydrochloride salt form II comprises 2 ⁇ 0.2°: 6.0, 6.5, 8.4, 11.7, 12.1, 13.2, 14.6, 15.7, 16.7, 17.7, 18.7, 19.1, 20.0, 22.5, Diffraction peaks of 23.0, 23.8, 24.5, and 25.6.
  • the present invention provides a process for the preparation of the salt form II of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethanol.
  • the hydrochloride salt form II of the compound of the formula (I) provided by the invention has good stability and is allowed to stand at 40 ° C for 1 month, and the degradation is ⁇ 0.5%.
  • the present invention provides the hydrochloride salt form III of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.1, 7.0, 9.2, 10.2 and 21.0;
  • the XRPD pattern of the hydrochloride salt form III comprises 2 ⁇ 0.2°: 6.1, 7.0, 9.2, 10.2, 12.4, 14.4, 16.4, 16.9, 18.6, 19.5, 21.0, 24.6, 25.6, and 26.2. Diffraction peaks.
  • the present invention provides a process for the preparation of the salt form III of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in dichloromethane.
  • the present invention provides the hydrochloride salt form IV of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.1, 7.8, 9.5, 11.9 and 25.0;
  • the XRPD pattern of the hydrochloride salt form IV comprises 2 ⁇ 0.2° of: 5.9, 6.1, 7.8, 8.8, 9.5, 10.0, 11.9, 12.4, 15.5, 21.2, 23.6, 25.0, 26.5 and 32.5. Diffraction peaks.
  • the present invention provides a process for the preparation of the salt form IV of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in acetonitrile.
  • the present invention provides a hydrochloride salt form V of the compound of formula (I).
  • the XRPD pattern of the hydrochloride salt form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.5, 12.0, 13.2, 16.5 and 23.6;
  • the XRPD pattern of the hydrochloride salt form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.5, 8.8, 11.5, 12.0, 13.2, 14.4, 14.8, 15.2, 16.5, 20.3, 21.3, 23.6. , 25.3 and 27.0 diffraction peaks.
  • the present invention provides a process for the preparation of the salt form V of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with hydrochloric acid in ethyl acetate.
  • the present invention provides a sulfate form of the compound of formula (I).
  • the present invention provides a sulfate form I of the compound of formula (I).
  • the XRPD pattern of the sulfate form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.6, 6.4, 7.6, 13.4 and 27.1;
  • the XRPD pattern of the sulfate form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.6, 6.4, 7.6, 11.3, 12.1, 12.4, 13.4, 14.1, 15.3, 18.1, 19.0, 20.9, Diffraction peaks of 21.5, 24.5, 24.9, and 27.1.
  • the present invention provides a process for the preparation of the sulfate form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in ethyl acetate.
  • the present invention provides a sulfate form II of the compound of formula (I).
  • the XRPD pattern of the sulfate form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.8, 6.1, 6.5, 9.0, 13.0 and 23.9;
  • the XRPD pattern of the sulfate form II of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 6.1, 6.5, 7.8, 9.0, 11.8, 13.0, 14.6, 15.4, 16.0, 16.6, 17.4, Diffraction peaks of 18.1, 19.8, 21.6, 22.1, 23.0, and 23.9.
  • the present invention provides a process for the preparation of the sulfate form II of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in acetonitrile.
  • the present invention provides a sulfate form III of the compound of formula (I).
  • the XRPD pattern of the sulfate form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.6, 7.8, 15.5, 18.1, 25.0 and 27.1;
  • the XRPD pattern of the sulfate form III of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.6, 7.8, 9.5, 11.5, 12.2, 12.6, 13.6, 14.3, 15.5, 17.1, 18.1, 18.7, Diffraction peaks of 19.1, 19.8, 21.1, 21.6, 23.2, 24.6, 25.0 and 27.1.
  • the present invention provides a process for the preparation of the sulfate form III of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in acetone.
  • the present invention provides a sulfate form IV of the compound of formula (I).
  • the XRPD pattern of the sulfate form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.2, 6.6, 9.8, 20.5 and 23.3;
  • the XRPD pattern of the sulfate form IV of the compound of the formula (I) comprises 2 ⁇ 0.2° of: 5.2, 6.6, 8.7, 9.8, 11.3, 13.4, 16.5, 20.5, 23.3, 25.4, 26.7 and 28.8. Diffraction peaks.
  • the invention provides a process for the preparation of the sulfate form IV of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with sulfuric acid in dichloromethane.
  • the present invention provides a sulfate form V of the compound of formula (I).
  • the XRPD pattern of the sulfate form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.8, 6.3, 13.5, 24.0 and 24.8;
  • the XRPD pattern of the sulfate form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 6.3, 13.5, 14.5, 14.9, 16.8, 17.4, 18.1, 19.4, 20.5, 20.9, 22.8, Diffraction peaks of 24.0, 24.8, 26.7, 28.3 and 31.8.
  • the present invention provides a process for the preparation of the sulfate form V of the compound of the formula (I), wherein the compound of the formula (I) is reacted with sulfuric acid in acetonitrile and stirred for a long period of time.
  • the present invention provides a crystalline form of the mesylate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.2, 7.8, 9.6, 13.8, 18.9 and 25.6;
  • the XRPD pattern of the methanesulfonate salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.2, 7.8, 9.6, 12.5, 13.8, 14.6, 15.4, 16.1, 18.9, 19.4, 20.5, Diffraction peaks of 21.0, 22.4, 23.3, 24.0, 25.1, 25.6, 26.6 and 27.9.
  • the present invention provides a process for the preparation of the methanesulfonate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with methanesulfonic acid in acetonitrile.
  • the present invention provides a crystalline form II of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.5, 8.2, 13.7, 17.3, 20.9 and 25.1;
  • the XRPD pattern of the methanesulfonate salt form II of the compound of the formula (I) comprises 2 ⁇ 0.2° of: 7.5, 8.2, 11.5, 13.7, 15.1, 17.3, 20.0, 20.9, 23.0, 25.1 and 28.9. Diffraction peaks.
  • the invention provides a preparation method of the methanesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is reacted with methanesulfonic acid in ethanol.
  • the methanesulfonate salt form II of the compound of the formula (I) provided by the present invention is a solvate crystal form, and the crystal contains ethanol and water.
  • the present invention provides a crystalline form III of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.2, 13.5, 16.3, 19.5, 22.0 and 24.2;
  • the XRPD pattern of the methanesulfonate salt form III of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.2, 6.9, 11.1, 12.5, 13.5, 14.7, 16.3, 17.2, 18.4, 19.5, 20.4, Diffraction peaks of 22.0, 24.2, 24.8, and 30.4.
  • the invention provides a preparation method of the methanesulfonate salt form III of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by crystallizing in a humidity of 92.5%.
  • the present invention provides a crystalline form IV of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.1, 9.0, 11.0, 13.6, 14.8, 22.3 and 23.8;
  • the XRPD pattern of the methanesulfonate salt form IV of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.1, 6.9, 9.0, 11.0, 13.6, 14.8, 18.4, 18.9, 20.6, 22.3, 23.8 and Diffraction peak of 25.4.
  • the invention provides a preparation method of the methanesulfonate salt form IV of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in isobutanol.
  • the methanesulfonate salt form IV of the compound of the formula (I) provided by the present invention is an isobutanol solvate crystal form.
  • the present invention provides a crystalline form V of the methanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.1, 7.9, 9.4, 15.9, 19.2 and 24.5;
  • the XRPD pattern of the methanesulfonate form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.1, 7.9, 9.4, 10.1, 12.2, 12.6, 13.3, 14.3, 15.9, 17.2, 19.1. Diffraction peaks of 21.8, 22.8, 23.7, 24.5, 27.3 and 29.1.
  • the invention provides a preparation method of the methanesulfonate salt form V of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in isopropanol.
  • the methanesulfonate form V of the compound of the formula (I) provided by the present invention is an isopropanol solvate crystal form.
  • the present invention provides a mesylate salt form VI of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form VI of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.6, 8.6, 13.7, 17.5, 22.1, 23.7 and 28.8;
  • the XRPD pattern of the methanesulfonate salt form VI of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.6, 8.6, 11.4, 13.7, 15.1, 17.5, 18.5, 18.8, 20.1, 21.1, 22.1, Diffraction peaks of 23.1, 23.7, 24.5, 25.7 and 28.8.
  • the invention provides a preparation method of the methanesulfonate salt form VI of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by beating and crystallizing in ethyl formate.
  • the mesylate salt form VI of the compound of the formula (I) provided by the present invention is an ethyl formate solvate crystal form.
  • the present invention provides a mesylate salt form VII of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form VII of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.2, 7.1, 10.4, 14.1 and 23.3;
  • the XRPD pattern of the methanesulfonate salt form VII of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.2, 7.1, 10.4, 12.0, 13.2, 14.1, 16.0, 17.2, 18.7, 23.3, and 30.2. Diffraction peak
  • the invention provides a preparation method of the methanesulfonate salt form VII of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in ethyl acetate for a long time.
  • the present invention provides the methanesulfonate salt form VIII of the compound of formula (I).
  • the XRPD pattern of the methanesulfonate salt form VIII of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.9, 6.4, 13.6, 16.9, 24.1 and 25.0;
  • the XRPD pattern of the mesylate salt form VIII comprises 2 ⁇ 0.2°: 5.9, 6.4, 13.6, 14.6, 15.1, 16.9, 17.6, 18.2, 19.6, 20.6, 21.0, 22.7, 24.1, 25.0. , diffraction peaks of 26.8, 28.4, and 31.9.
  • the invention provides a preparation method of the methanesulfonate salt form VIII of the compound of the formula (I), wherein the methanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in acetone for a long time.
  • the methanesulfonate salt form VIII of the compound of the formula (I) provided by the invention contains no solvent and melts and degrades at 172 ° C, and the crystal form has good stability under the conditions of high humidity RH 92.5% and high temperature 40 ° C. After storage for 1 month, the related substances increased by ⁇ 0.5%.
  • the present invention provides a crystalline form of the besylate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.4, 5.9, 7.1, 10.4, 14.8, 17.6 and 21.9;
  • the XRPD pattern of the benzenesulfonate salt form I comprises 2 ⁇ 0.2°: 5.4, 5.9, 6.8, 7.1, 8.3, 8.7, 10.4, 11.7, 14.0, 14.8, 15.1, 17.6, 20.9, 21.9 , diffraction peaks of 23.7, 24.8, and 26.6.
  • the invention provides a preparation method of the benzenesulfonate salt form I of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in ethanol.
  • the present invention provides a crystalline form II of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 4.4, 6.0, 9.3, 11.5, 17.5, 21.0 and 26.0;
  • the XRPD pattern of the benzenesulfonate salt form II comprises 2 ⁇ 0.2°: diffraction of 4.4, 6.0, 9.3, 11.5, 14.8, 15.3, 17.5, 20.0, 21.0, 21.9, 22.7, 24.6 and 26.0. peak.
  • the invention provides a preparation method of the benzenesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in tetrahydrofuran.
  • the present invention provides a crystalline form III of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form III of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.7, 8.3, 8.6, 17.2, 23.2 and 26.0;
  • the XRPD pattern of the benzenesulfonate salt form III comprises 2? ⁇ 0.2°: diffraction of 7.7, 8.3, 8.6, 11.6, 13.8, 14.5, 17.2, 18.3, 18.9, 20.8, 21.8, 23.2 and 26.0. peak.
  • the invention provides a preparation method of the benzenesulfonate salt form III of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in dichloromethane.
  • the present invention provides a crystalline form IV of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form IV of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.7, 6.4, 13.0, 14.4 and 23.8;
  • the XRPD pattern of the benzenesulfonate salt form IV of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.7, 6.4, 12.0, 13.0, 14.4, 15.6, 16.5, 17.5, 18.6, 21.0, 21.7, Diffraction peaks of 23.2, 23.8, 26.0, 26.6, and 30.0.
  • the invention provides a preparation method of the benzenesulfonate salt form IV of the compound of the formula (I), wherein the benzenesulfonate of the compound of the formula (I) is obtained by stirring and crystallizing in acetonitrile for a long time.
  • the present invention provides a form V of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate crystal form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.7, 7.5, 10.3, 14.3 and 25.1;
  • the XRPD pattern of the benzenesulfonate crystal form V comprises 2 ⁇ 0.2°: 5.7, 7.5, 10.3, 11.0, 11.3, 11.7, 13.8, 14.3, 16.3, 16.6, 17.8, 18.3, 19.0, 20.1 , diffraction peaks of 23.4, 25.1 and 27.5.
  • the invention provides a preparation method of the benzenesulfonate salt form V of the compound of the formula (I), wherein the benzenesulfonate of the compound of the formula (I) is obtained by stirring and crystallizing in a 75% aqueous solution of ethanol for a long time.
  • the present invention provides a crystalline form VI of the besylate salt of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form VI of the compound of the formula (I) contains 2 ⁇ 0.2°: diffraction peaks of 6.0, 7.4, 13.5, 18.6, 23.6 and 24.5;
  • the XRPD pattern of the benzenesulfonate salt form VI of the compound of the formula (I) comprises 2 ⁇ 0.2°: 6.0, 7.4, 11.6, 12.2, 12.8, 13.5, 14.8, 16.5, 17.5, 18.6, 20.4, Diffraction peaks of 21.0, 21.6, 22.7, 23.6, 24.5, 25.9, 26.7 and 27.5.
  • the invention provides a preparation method of the benzenesulfonate salt form VI of the compound of the formula (I), wherein the compound of the formula (I) is reacted with benzenesulfonic acid in acetone.
  • the benzenesulfonate salt form VI of the compound of the formula (I) provided by the invention has no solvent and has a melting point of 162 ° C, which is very suitable for the development of pharmaceutical preparations, the highest yield of the preparation process is 95%, and the preparation process has good reproducibility. It is especially suitable for industrial production.
  • the present invention provides a benzenesulfonate salt form VII of the compound of formula (I).
  • the XRPD pattern of the benzenesulfonate salt form VII of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.9, 7.1, 9.7, 15.0, 16.4 and 23.7;
  • the XRPD pattern of the benzenesulfonate salt form VII of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.9, 7.1, 9.7, 11.9, 12.9, 13.4, 15.0, 16.4, 18.3, 18.8, 20.5, Diffraction peaks of 21.2, 21.9, 22.8, and 23.7.
  • the invention provides a preparation method of the benzenesulfonate salt form VII of the compound of the formula (I), wherein the besylate salt of the compound of the formula (I) is obtained by crystallizing in 92.5% RH.
  • the present invention provides a crystalline form of the ethanesulfonate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the ethanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the ethyl sulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.5, 8.3 and 17.9;
  • the XRPD pattern of the ethyl sulfonate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.5, 8.3, 10.5, 12.9, 17.9, 23.5 and 25.0.
  • the invention provides a preparation method of the ethyl sulfonate salt form I of the compound of the formula (I), which is obtained by reacting the compound of the formula (I) with ethanesulfonic acid in ethanol.
  • the present invention provides a crystalline form II of the ethanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the ethanesulfonate salt form II of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 6.0, 6.6, 12.1 and 24.1;
  • the XRPD pattern of the ethanesulfonate salt form II of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.8, 6.0, 6.6, 8.5, 12.1, 13.3, 14.7, 15.4, 16.3, 16.8, 17.3, Diffraction peaks of 19.1, 22.1, 23.3 and 24.1.
  • the invention provides a preparation method of the ethyl sulfonate salt form II of the compound of the formula (I), wherein the ethanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in ethyl acetate for a long time.
  • the present invention provides a crystalline form III of the ethanesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the ethanesulfonate salt form III of the compound of the formula (I) contains 2 ⁇ 0.2°: diffraction peaks of 6.0, 7.6, 12.2, 13.6 and 18.3;
  • the XRPD pattern of the ethanesulfonate salt form III contains diffraction peaks of 2 ⁇ 0.2°: 6.0, 7.6, 9.4, 12.2, 13.6, 14.4, 15.2, 16.6, 17.2, 18.4, 19.3 and 20.4.
  • the invention provides a preparation method of the ethyl sulfonate salt form III of the compound of the formula (I), wherein the ethanesulfonate salt of the compound of the formula (I) is obtained by stirring and crystallizing in dichloromethane for a long time.
  • the present invention provides a crystalline form of the oxalate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the compound of formula (I).
  • the XRPD pattern of the oxalate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 4.1, 6.9, 7.9, 14.5, 19.4, 23.8 and 27.0;
  • the XRPD pattern of the oxalate salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 4.1, 6.9, 7.9, 11.7, 12.2, 13.0, 13.9, 14.5, 15.0, 16.4, 17.6, 19.4. , diffraction peaks of 20.3, 21.0, 23.8, 25.5, 26.0, and 27.0.
  • the present invention provides a process for the preparation of the oxalate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with oxalic acid in dichloromethane.
  • the present invention provides a crystalline form I of the compound of formula (I) having a melting point of about 150 °C.
  • the present invention provides a crystalline form II of the compound of formula (I).
  • the XRPD pattern of the compound oxalate crystal form II of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 4.0, 6.8, 7.7, 8.1, 16.7 and 23.7;
  • the XRPD pattern of the compound oxalate crystal form II of the formula (I) comprises 2 ⁇ 0.2°: 4.0, 6.8, 7.7, 8.1, 14.6, 16.7, 17.4, 17.9, 20.9, 21.4, 22.1, 22.7. , diffraction peaks of 23.7 and 27.7.
  • the invention provides a preparation method of the compound (I) compound oxalate crystal form II, wherein the compound oxalate salt of the formula (I) is obtained by beating and crystallizing in acetone.
  • the present invention provides a crystalline form II of the compound of formula (I) having a melting point of about 154 °C.
  • the present invention provides a crystalline form of the maleate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the maleate salt of the compound of formula (I).
  • the XRPD pattern of the maleate salt form I of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 5.6, 8.1, 10.8, 13.8, 23.0 and 26.3;
  • the XRPD pattern of the maleate salt form I of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.6, 6.4, 8.1, 10.8, 11.6, 12.4, 12.9, 13.3, 13.8, 14.7, 15.5, Diffraction peaks of 16.7, 17.4, 17.8, 18.0, 18.6, 20.1, 21.1, 22.6, 23.0, 23.8, 24.8, 26.3 and 28.1.
  • the present invention provides a process for the preparation of the crystalline form I of the compound of the formula (I), wherein the compound of the formula (I) is co-crystallized with maleic acid in a dichloromethane/ethyl acetate system.
  • the invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in ethyl acetate and stirred at room temperature for 7 days.
  • the maleate salt form I is obtained.
  • the invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in dichloromethane, and ethyl acetate and malay are added. The crystal form I seed crystal is crystallized to obtain the maleate salt form I.
  • the invention also provides another preparation method of the compound (I) maleate salt form I, in particular, the compound of the formula (I) and maleic acid are placed in dichloromethane, and n-heptane and malay are added. The crystal form I seed crystal was stirred to obtain a crystal form I sample.
  • the present invention provides a compound of formula (I), maleate salt Form I, having a maleic acid content of from about 27% to about 33%, preferably from about 29% to about 31%, most preferably from about 30%.
  • the compound of the formula (I) provided by the present invention is free of water and an organic solvent, and is allowed to stand under high humidity (RH 92.5%) and high temperature (40 ° C) conditions for 6 months without substantially degrading.
  • the present invention provides a compound of formula (I), maleate salt form I, having a melting point of 114 °C.
  • the compound of the formula (I) provided by the invention has simple preparation process and good process reproducibility, and is particularly suitable for industrial production and pharmaceutical preparation research.
  • the present invention provides a crystalline form of the p-toluenesulfonate salt of the compound of formula (I).
  • the present invention provides a crystalline form I of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the p-toluenesulfonate salt form I of the compound of the formula (I) contains diffraction peaks of 2 ⁇ 0.2°: 7.6, 13.5, 15.0, 20.6 and 23.5;
  • the XRPD pattern of the crystalline form I of the p-toluenesulfonate salt of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.6, 8.5, 10.1, 11.9, 13.0, 13.5, 15.0, 16.5, 17.0, 17.4, 18.4. Diffraction peaks of 18.7, 20.6, 20.9, 23.5, 24.1, 25.7 and 26.6.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form I of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in ethyl acetate.
  • the present invention provides a crystalline form II of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form II comprises 2 ⁇ 0.2°: diffraction peaks of 7.5, 8.1, 13.1, 20.7 and 22.9;
  • the XRPD pattern of the p-toluenesulfonate salt form II of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.5, 8.1, 13.1, 13.5, 16.5, 16.9, 17.7, 19.9, 20.7, 21.1, 22.9. , diffraction peaks of 24.9, 25.5, and 28.7.
  • the invention provides a preparation method of the p-toluenesulfonate salt form II of the compound of the formula (I), wherein the compound of the formula (I) is obtained by beating and crystallizing the p-toluenesulfonate in ethanol.
  • the present invention provides a crystalline form III of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the compound p-toluenesulfonate crystal form III of the formula (I) comprises diffraction peaks of 2 ⁇ 0.2°: 8.3, 12.8, 14.7, 16.6 and 24.3;
  • the XRPD pattern of the p-toluenesulfonate salt form III of the compound of the formula (I) comprises 2 ⁇ 0.2°: 5.4, 6.9, 8.3, 8.8, 9.1, 10.5, 10.8, 11.4, 12.1, 12.8, 14.7. Diffraction peaks of 15.5, 16.6, 17.2, 17.8, 18.5, 18.8, 19.3, 19.9, 20.4, 22.1, 22.4, 23.4, 23.9, 24.3, 25.4, 25.8, 26.8, 27.5, 28.4 and 29.6.
  • the invention provides a preparation method of the p-toluenesulfonate salt form III of the compound of the formula (I), wherein the compound of the formula (I) is obtained by crystallizing the p-toluenesulfonate in water for a long time.
  • the present invention provides a crystalline form IV of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IV comprises 2 ⁇ 0.2° as diffraction peaks of 7.3, 14.4, 21.2, 23.5 and 25.3;
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IV comprises 2 ⁇ ⁇ 0.2°: 5.7, 7.3, 10.1, 10.6, 11.7, 14.4, 16.1, 16.6, 17.2, 18.5, 18.9 Diffraction of 19.9, 20.6, 21.2, 22.3, 22.9, 23.5, 24.4, 25.3, 25.8, 26.9, 27.4, 28.1, 29.2, 30.1, 31.0, 31.6, 32.5, 33.1, 33.6, 34.5, 35.5, 367, 38.9 and 42.7 peak.
  • the invention provides a preparation method of the p-toluenesulfonate salt form IV of the compound of the formula (I), wherein the compound of the formula (I) is obtained by slurrying and translating p-toluenesulfonate in ethyl acetate.
  • the present invention provides a crystalline form V of the p-toluenesulfonate salt of the compound of formula (I).
  • the XRPD pattern of the tosylate salt form V of the compound of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 8.1, 10.2, 11.0, 19.4 and 24.1;
  • the XRPD pattern of the p-toluenesulfonate crystal form V of the compound of the formula (I) comprises 2 ⁇ 0.2°: 8.1, 8.5, 9.0, 10.2, 11.0, 13.8, 14.8, 16.6, 17.0, 17.5, 18.3. Diffraction peaks of 19.4, 20.6, 22.1, 23.0, 24.1, 25.8, 28.1, 30.1 and 30.7.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form V of the compound of the formula (I), wherein the compound of the formula (I) is p-crystallized by p-toluenesulfonate in dichloromethane/ethyl acetate.
  • the present invention provides a crystalline form VI of the compound p-toluenesulfonate of formula (I).
  • the XRPD pattern of the compound p-toluenesulfonate form VI of the formula (I) contains 2 ⁇ 0.2° as diffraction peaks of 7.2, 12.5, 16.5 and 21.0;
  • the XRPD pattern of the compound of the formula (I) on the p-toluenesulfonate form VI comprises 2 ⁇ 0.2°: 6.8, 7.2, 7.7, 10.0, 10.4, 11.6, 12.5, 14.3, 16.5, 17.1, 17.5. Diffraction peaks of 18.2, 19.2, 19.7, 21.0, 21.7, 23.5, 23.7, 24.4, 25.3, 26.8 and 29.4.
  • the invention provides a preparation method of the p-toluenesulfonate salt form VI of the compound of the formula (I), wherein the compound of the formula (I) is obtained by slurrying and translating the p-toluenesulfonate in acetone/ethyl acetate.
  • the present invention provides a compound of formula (I) p-toluenesulfonate Form VII.
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VII comprises 2 ⁇ 0.2°: diffraction peaks of 5.7, 6.9, 9.9 and 17.6;
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VII comprises 2 ⁇ 0.2°: 5.7, 6.9, 7.4, 8.7, 9.9, 11.5, 12.5, 14.6, 15.7, 17.6, 23.6. , diffraction peaks of 24.7 and 26.5.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form VII of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in ethanol.
  • the present invention provides a compound of formula (I) p-toluenesulfonate Form VIII.
  • the XRPD pattern of the compound of formula (I) p-toluenesulfonate Form VIII comprises 2 ⁇ 0.2°: diffraction peaks of 4.2, 5.9, 7.2, 9.0 and 25.3;
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form VIII comprises 2 ⁇ ⁇ 0.2°: 4.2, 5.9, 7.2, 9.0, 10.3, 11.0, 14.3, 15.2, 16.6, 18.9, 19.7 Diffraction peaks of 19.9, 21.0, 22.1, 23.6, 25.3, 26.2, 29.5 and 31.1.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form VIII of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in acetone.
  • the present invention provides a crystalline form IX of the compound p-toluenesulfonate of formula (I).
  • the XRPD pattern of the compound of formula (I) for p-toluenesulfonate Form IX comprises 2 ⁇ 0.2°: diffraction peaks of 7.0, 7.7, 9.4, 12.9 and 15.4;
  • the XRPD pattern of the p-toluenesulfonate salt form IX of the compound of the formula (I) comprises 2 ⁇ 0.2°: 7.0, 7.7, 9.4, 10.8, 12.2, 12.9, 13.7, 15.4, 18.0, 20.5, 21.9. , diffraction peaks of 23.2, 26.7 and 28.0.
  • the present invention provides a process for the preparation of the p-toluenesulfonate salt form IX of the compound of the formula (I), which is obtained by reacting a compound of the formula (I) with p-toluenesulfonic acid in methanol.
  • the salts of the present invention have good physicochemical properties, especially in terms of solubility, stability and wettability, and particularly preferred salts of the present invention Its crystal form is particularly excellent in the above properties.
  • the crystal form of the invention has good stability, no hygroscopicity, good solubility, good adaptability in the preparation process, good drug dissolution behavior, and good bioavailability of the drug in the body.
  • the corresponding crystal form preparation process is simple, the yield is high, and it is suitable for industrial production. Therefore, the salt and crystal form of the compound of the formula (I) of the present invention are very suitable for pharmaceutical preparation applications and have good clinical application prospects. ⁇
  • Fig. 1 is an X-ray powder diffraction pattern of the hydrochloride salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 2 is an X-ray powder diffraction pattern of the hydrochloride salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 3 is an X-ray powder diffraction pattern of the hydrochloride salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 5 is an X-ray powder diffraction pattern of the hydrochloride salt form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 6 is an X-ray powder diffraction pattern of the sulfate form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 7 is an X-ray powder diffraction pattern of the sulfate form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 8 is an X-ray powder diffraction pattern of the sulfate form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 9 is an X-ray powder diffraction pattern of the sulfate form IV of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 10 is an X-ray powder diffraction pattern of the sulfate form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 11 is an X-ray powder diffraction pattern of the mesylate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 12 is a DSC chart of the methanesulfonate salt form I of the compound of formula (I);
  • Figure 13 is a TGA spectrum of the mesylate salt form I of the compound of formula (I);
  • Fig. 14 is an X-ray powder diffraction pattern of the mesylate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 15 is an X-ray powder diffraction pattern of the mesylate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 16 is an X-ray powder diffraction pattern of the mesylate salt form IV of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 17 is an X-ray powder diffraction pattern of the methanesulfonate crystal form V of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 18 is an X-ray powder diffraction pattern of the mesylate salt form VI of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Fig. 19 is an X-ray powder diffraction pattern of the mesylate salt form VII of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 20 is an X-ray powder diffraction pattern of the mesylate salt form VIII of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 21 is a DSC chart of the methanesulfonate salt form VIII of the compound of formula (I);
  • Figure 22 is a TGA spectrum of the methanesulfonate salt form VIII of the compound of formula (I);
  • Figure 23 is an X-ray powder diffraction pattern of the form I of the besylate salt of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Fig. 24 is an X-ray powder diffraction pattern of the benzenesulfonate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 25 is an X-ray powder diffraction pattern of the benzenesulfonate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 26 is an X-ray powder diffraction pattern of the form of the besylate salt of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 27 is an X-ray powder diffraction pattern of the form of the besylate salt form V of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 28 is an X-ray powder diffraction pattern of the form of the besylate salt form VI of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 29 is an X-ray powder diffraction pattern of the benzenesulfonate salt form VII of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 30 is an X-ray powder diffraction pattern of the ethanesulfonate salt form I of the compound of the formula (I), wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 31 is an X-ray powder diffraction pattern of the ethanesulfonate salt form II of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 32 is an X-ray powder diffraction pattern of the ethanesulfonate salt form III of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 33 is an X-ray powder diffraction pattern of the oxalate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 34 is a DSC chart of the oxalate salt form I of the compound of formula (I);
  • Figure 35 is a TGA spectrum of the oxalate salt form I of the compound of formula (I);
  • Figure 36 is an X-ray powder diffraction pattern of the compound oxalate crystal form II of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 37 is a DSC spectrum of the compound oxalate salt form II of the formula (I);
  • Figure 38 is a TGA pattern of the oxalate salt form II of the compound of formula (I);
  • Figure 39 is an X-ray powder diffraction pattern of the maleate salt form I of the compound of the formula (I), wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 40 is a DSC spectrum of the maleate salt form I of the compound of formula (I)
  • Figure 41 is an X-ray powder diffraction pattern of the compound (I) p-tolylate Form I, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 42 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form II, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 43 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form III, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 44 is an X-ray powder diffraction pattern of the compound of the formula (I) versus toluene salt form IV, wherein the vertical axis represents the peak intensity (cps) and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 45 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form V, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 46 is an X-ray powder diffraction pattern of the compound (I)-p-tolylate Form VI, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 47 is an X-ray powder diffraction pattern of the compound of the formula (I) versus toluene salt crystal form VII, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 48 is an X-ray powder diffraction pattern of the compound of the formula (I), p-toluate, Form VIII, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • Figure 49 is an X-ray powder diffraction pattern of the compound of the formula (I), p-toluate, Form IX, wherein the vertical axis represents peak intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ [°]).
  • the second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone
  • the third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate
  • EtOAc EtOAc
  • Step 5 (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide
  • oxalate salt of the compound of the formula (I) was weighed into the reactor, and 10.0 mL of acetone was added thereto at room temperature, and the mixture was stirred for 3 days, and the suspension was filtered to obtain a solid, i.e., oxalate crystal form II.
  • Example 35 Preparation of the crystalline form I of the p-toluenesulfonate salt of the compound of formula (I)
  • the compound of formula (I) is p-toluenesulfonate Form I.
  • the sample of the methanesulfonate salt form VIII and the maleate salt form I of the compound of the formula (I) provided by the present invention is placed under the conditions of high temperature 40 ° C and high humidity (RH 92.5%) at 0, 1, respectively. At 2, 3, and 6 months, samples were taken to investigate the relevant substances. The specific test results are shown in Table 2.
  • TR-FRET fluorescence resonance energy transfer
  • Adding 1 to 5 uL of the substrate mixture comprises a final concentration of the substrate polypeptide of 5 to 50 nM and a final concentration of ATP of 10 to 200 uM.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the enzymatic activities of the specific examples are shown in Table 3.
  • TR-FRET fluorescence resonance energy transfer
  • Adding 1 to 5 uL of the substrate mixture comprises a final concentration of the substrate polypeptide of 5 to 50 nM and a final concentration of ATP of 10 to 200 uM.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the enzymatic activities of the specific examples are shown in Table 3.
  • the method of the present study the inhibition of a test compound CellTiter-Glo proliferation of Hep 3B cells, derived compounds inhibit cell proliferation and half maximal inhibitory concentration IC 50 activity.
  • the plate reader measures the chemiluminescence signal values of the plates.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the cell activity of the specific examples is shown in Table 4.
  • the method of the present study the inhibition of a test compound on the CellTiter-Glo HuH-7 cell proliferation, and to obtain the compound inhibited cell proliferation half maximal inhibitory concentration IC 50 activity.
  • the plate reader measures the chemiluminescence signal values of the plates.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the cell activity of the specific examples is shown in Table 4.
  • the method of the present study the inhibition of a test compound on the CellTiter-Glo SK-HEP-1 cell proliferation, the compounds inhibit cell proliferation and draw half maximal inhibitory concentration IC 50 activity.
  • the cells/mL were cultured in an incubator for 16 to 24 hours (37 ° C, 5% CO 2 ).
  • the plate reader measures the chemiluminescence signal values of the plates.
  • the IC 50 of the compound was obtained by curve fitting according to the inhibition rates of different concentrations.
  • the cell activity of the specific examples is shown in Table 4.
  • the rat pharmacokinetic test of the preferred embodiment of the present invention was carried out using SD rats (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • ⁇ Mode of administration single oral administration.
  • Formulation formulation 0.5% CMC and 1% Tween 80, sonicated.
  • ⁇ Sampling points 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.
  • the plasma sample was added to 160 uL of acetonitrile precipitate in 40 ⁇ L, and mixed for 500 to 2000 ⁇ g for 5 to 20 minutes.
  • Time/minute Liquid A B liquid 0.01 80% 20% 0.5 80% 20% 1.2 10% 90% 2.6 10% 90% 2.7 80% 20% 3.8 80% 20%
  • FBS fetal bovine serum
  • the cells are covered with 80-90% of the bottom of the culture flask, they are passaged. After passage, the cells are continuously cultured in a CO2 incubator. This process is repeated until the number of cells meets the in vivo efficacy requirements.
  • the cultured cells were collected, counted by a fully automatic cell counter, and the cells were resuspended in PBS according to the counting results to prepare a cell suspension (density: 7 ⁇ 10 7 /mL), which was placed in an ice box for use.
  • mice were labeled with a one-time large mouse universal ear tag before inoculation, and the skin of the inoculated site was disinfected with 75% medical alcohol.
  • test nude mice were inoculated in turn (the inoculation site was placed subcutaneously inoculated with 0.1 mL of cell suspension on the right side of the right side of the nude mouse).
  • tumors were counted on days 14-16 after inoculation, and tumor size was calculated.
  • tumor volume (mm3) length (mm) ⁇ width (mm) ⁇ width (mm) / 2
  • the administration of the test drug (administration method: oral administration, administration dose: 30 mg/kg, administration volume: 10 mL/kg, administration frequency: 2 times/day, administration period: 14 days) , solvent: 0.5% CMC / 1% Tween 80).
  • the tumor was dosed twice a week after the test drug was administered, and weighed.

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Abstract

L'invention concerne un sel et un cristal d'inhibiteur de FGFR4, un procédé de préparation et une utilisation associés. En particulier, la présente invention concerne une forme cristalline d'un sel pharmaceutiquement acceptable d'un composé de formule (I) et un procédé de préparation associé, ainsi qu'une composition pharmaceutique contenant une quantité thérapeutiquement efficace de la forme cristalline et son utilisation dans le traitement de cancers.
PCT/CN2018/112891 2017-10-31 2018-10-31 Sel et cristal d'inhibiteur de fgfr4, son procédé de préparation et son utilisation WO2019085927A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015059668A1 (fr) * 2013-10-25 2015-04-30 Novartis Ag Dérivés pyridyle bicycliques à anneaux fusionnés utilisés en tant qu'inhibiteurs de fgfr4
WO2016151501A1 (fr) * 2015-03-25 2016-09-29 Novartis Ag Combinaisons pharmaceutiques
WO2016151500A1 (fr) * 2015-03-25 2016-09-29 Novartis Ag Particules de n-(5-cyano-4-((2-méthoxyéthyl)amino)pyridin-2-yl)-7-formyl-6-((4-méthyl-2-oxopipérazin-1-yl)méthyl)-3,4-dihydro-1,8-naphthyridine-1(2h)-carboxamide
WO2017198149A1 (fr) * 2016-05-20 2017-11-23 江苏豪森药业集团有限公司 Inhibiteur de fgfr4, procédé pour sa préparation et applications correspondantes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015059668A1 (fr) * 2013-10-25 2015-04-30 Novartis Ag Dérivés pyridyle bicycliques à anneaux fusionnés utilisés en tant qu'inhibiteurs de fgfr4
WO2016151501A1 (fr) * 2015-03-25 2016-09-29 Novartis Ag Combinaisons pharmaceutiques
WO2016151500A1 (fr) * 2015-03-25 2016-09-29 Novartis Ag Particules de n-(5-cyano-4-((2-méthoxyéthyl)amino)pyridin-2-yl)-7-formyl-6-((4-méthyl-2-oxopipérazin-1-yl)méthyl)-3,4-dihydro-1,8-naphthyridine-1(2h)-carboxamide
WO2017198149A1 (fr) * 2016-05-20 2017-11-23 江苏豪森药业集团有限公司 Inhibiteur de fgfr4, procédé pour sa préparation et applications correspondantes

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